No abstract

Background: Approximately 30% of TNBCs are characterized by microarray as claudin-low, mesenchymal or mesenchymal stem cell-like and, unlike basal TNBCs, these tumors frequently harbor aberrations in the PI3K/AKT/mTOR axis, raising the possibility of targeting this axis to enhance chemotherapy response. Assays to clinically identify mesenchymal TNBCs are under development, but published results confirm that up to 30% are metaplastic breast cancers (MpBCs), a chemo-refractory group of tumors that contain a mixture of epithelial and mesenchymal components, making them identifiable by microscopy. As such, MpBCs serve as surrogates of response for potential regimens to treat mesenchymal TNBC. Methods: Patients (pts) with advanced TNBC (N=64) were treated with liposomal doxorubicin (D), bevacizumab (A) and the mTOR inhibitors temsirolimus (T) or everolimus (E). D and A were administered IV on day 1 with T (IV on days 1, 8 and 15) or E (continuous daily oral administration) using 21 day cycles. Response was assessed every 6 weeks using RECIST. When available, archived tissue was evaluated for aberrations in the PI3K pathway using standard assays. Results: Fifty-two MpBC pts were treated with DAT (N=39) or DAE (N=13). Median age was 58 (range 37-79); median # of prior regimens for metastatic disease was 1 (range 0-5). The objective response rate (ORR) was 21% [complete response (CR)=4 (8%); partial response (PR)=7 (13%)] and 10 (19%) pts had stable disease (SD)≥6 months for a clinical benefit rate (CBR) of 40%. Tissue was available for testing in 43 pts and 32 (74%) had a PI3K pathway activating aberration (Table 1). Response According to PI3K Pathway AberrationPI3K Pathway AberrationN (%)CRPRSD≥6monthsCBRORRAny PI3K Pathway Aberration*32 (74)46444%31%PIK3CA Mutation19 (59)23447%26%p.H1047R12 (38)21350%25%p.E545K6 (19)02150%33%p.G1007R1 (3)010100%100%p.E545A1 (3)0000%0%p.H1047Y1 (3)0000%0%p.K111E1 (3)0000%0%p.E542K1 (3)0000%0%PIK3CA Amplification1 (3)010100%100%PTEN Mutation5 (16)0000%0%PTEN Loss5 (16)02040%40%AKT1 p.E17K Mutation2 (6)0000%0%AKT2 Amplification1 (3)100100%100%PIK3R1 Mutation2 (6)01050%50%NF2 Mutation1 (3)100100%100%No PI3K Pathway Aberration11 (26)00545%0%*Some tumors had >1 aberration detected PI3K pathway activation was associated with a significant improvement in ORR (31 vs 0%; P=0.043) but not CBR (44 vs 45%; P=1.000) or progression-free survival (median 5.1 vs 2.9 months; P=0.352). A pt with 5 year+ durable CR (on maintenance everolimus) had a mutation in NF2. To emphasize the importance of pt selection, it is notable that 12 pts with non-metaplastic TNBC were also treated with DAT, and only 1 pt had a response (CR/PR=1; SD≥6 months=0), for a CBR that was significantly worse than pts with MpBC (8 vs 40%; P=0.045). Conclusions: Using MpBC as a surrogate of response, DAT/DAE has significantly better activity in mesenchymal compared to non-selected TNBC. Response is enhanced in pts with PI3K pathway activation. DAT/DAE should be tested in non-metaplastic, mesenchymal TNBC once a diagnostic assay is available. Citation Format: Basho RK, Gilcrease M, Murthy RK, Helgason T, Booser DJ, Karp DD, Meric-Bernstam F, Wheler JJ, Valero V, Albarracin C, Litton J, Chavez-MacGregor M, Ibrahim NK, Murray JL, Koenig KB, Hong D, Subbiah V, Kurzrock R, Janku F, Moulder S. Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer (TNBC): Evidence of efficacy and proof of concept from a phase I trial with dose expansion of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-02.

Background: Neoadjuvant chemotherapy (NACT) is an integral component for locally advanced and large operable breast cancer. The sequence of taxanes followed by anthracyclines has been the standard of care for almost 20 years. Eribulin (E) is a synthetic analogue of halichondrin B with distinct mechanism of action as microtubule dynamics inhibitor. The FDA approved E in 11/2010 for the treatment of patients (pts) with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Research Hypothesis: Sequential administration of eribulin followed by FAC/FEC-regimen, would have greater pathologic complete response (pCR) rate than sequential administration of paclitaxel followed by FAC/FEC-regimen as primary systemic therapy for woman with operable breast cancer. Methods: This is a phase II, randomized, single institution, open label study. Pts were randomized 1:1 to receive E (1.4 mg/m2 d1 and d8 q 21 days x 4) or paclitaxel (P) (80 mg/m2 weekly x12). Both arms received FAC/FEC regimen x 4 doses followed by surgery. Eligible pts were women age 18 or older, Karnosfky PS 80 – 100, histologically confirmed invasive breast cancer, clinical T2-T3, N0-3, M0, HER2-negative. Baseline LVEF of > 50% and normal hematology, liver and kidney laboratory function tests. Primary endpoint was pathologic complete response (pCR/RCB-0) assessed by residual cancer burden (RCB). [Symmans F, 2007]. This protocol (2012-0167) IRB of The University of Texas, MD Anderson Cancer Center. Results: A preplanned interim analysis aimed to validate trial assumption was conducted after treatment of 54 randomized pts. Between 8/2012 to 7/2014, 54 pts were randomized and 49 were evaluable for pCR(27 P arm and 22 E arm). Tumor response by RCB is shown in the table. pCR rates were 30% and 4.5% in the P and E arm, respectively. Table 1.ResponsePaclitaxel - FAC/FEC Arm (N=27)Eribulin - FAC/FEC Arm (N=22)RCB 0 (pCR)8 (30%)1 (4.5%)RCB I6 (22.2%)1 (4.5%)RCB II9 (33%)10 (45%)RCB III4 (14.8%)10 (45%) 53 pts were evaluable for toxicity. The combination was safe with mostly grade 1 and 2 toxicities in both arms. In the P arm grade 3 peripheral neuropathy and neutropenia was seen in 3% and 7%, respectively. In the E arm one patient died due to multiorgan failure during cycle 1. There was no other grade 3-5 toxicity. Biomarker analysis using CTCs by AdnaTest Breast were evaluated in 39 pts at baseline. 5/39 pts were positive for CTCs. 3 pts had transcripts for EpCAM, 1 for Muc-1 and another had both. 30 pts had an additional sample post therapy. 2 pts were positive for CTC at baseline as well as at follow up (FU) visit at 180 days. None of the samples showed CTC-EMT at baseline or at FU visits. Conclusions: The interim analysis demonstrated that E arm lead to significantly lower pCR/RCB1 rate compared to P arm. Ongoing biomarker analyses include TIL, hot spot mutation analysis (HSMA) and molecular inversion probes (MIP) will be presented at the time of the meeting. Clinical trial information: NCT01593020. Citation Format: Alvarez RH, Koenig KB, Ensor JE, Ibrahim NK, Chavez-MacGregor M, Litton JK, Schwartz Gomez JK, Cyriac A, Krishnamurty S, Caudle AS, Shaitelman SF, Whitman GJ, Booser DJ, Reuben JM, Valero V. A randomized phase II neoadjuvant (NACT) study of sequential eribulin followed by FAC/FEC-regimen compared to sequential paclitaxel followed by FAC/FEC-regimen in patients (pts) with operable breast cancer not overexpressing HER-2. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-04.

Background. Guidelines by the American Society of Clinical Oncology and the College of American Pathologists recently recommended that estrogen receptor (ER) status should be considered positive if 1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. Historically, 10% nuclear staining defined ER-positive status and impacted decision-making regarding endocrine therapy. Currently, no optimal threshold exists for ER either by clinically validating patient outcomes in prospective clinical trials or independently validated from systematically collected archived specimens from randomized clinical trials. In this study, we examined patient, tumor and treatment differences among patients by ER status: ER-positive ≥10%, ER-positive 1–10% and ER negative (<1%). We compared recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) among patients with different ER staining categories and adjusted by clinical stage, adjuvant chemo and endocrine therapy. Method. Patients with primary breast carcinoma treated at our center who had complete ER status from January 1990 to December 2011 were included in this study. Patients were excluded if they presented with recurrent or metastatic disease. For statistical analyses, patients who underwent surgery for breast cancer were separated into three groups: ER-positive ≥10%, ER-positive 1–10% and ER negative. Analyses comparing various clinical and pathologic characteristics among patients with different ER status were performed. Survival rates were calculated by the Kaplan-Meier method. Result. Patients whose tumors were ER-positive 1–10% (2.7%) were younger (median age 53 Vs. 56 years, P < 0.0001), more likely to have invasive ductal carcinoma histology with more advanced disease (clinical stage II/III 50.4% Vs. 37.3%, p < 0.0001), and were more likely to receive neoadjuvant chemotherapy (40.9% vs. 25.6%, P < 0.0001), adjuvant chemotherapy (45.5% vs. 31.2%, P < 0.0001), and less likely to receive adjuvant endocrine therapy (19.5% vs. 78.6%, P < 0.0001) compared to patients with ER-positive tumors ≥ 10%. They were also more likely to have HER-2-positive (29.1% vs. 13.4%, P < 0.0001) and grade III disease (82.1% vs. 29.6%, P < 0.0001). Compared to patients with ER negative, patients with ER-positive 1–10% had earlier stage disease (clinical stage II/III 50.4% Vs. 59.3%, p = 0.01), were less likely to receive neoadjuvant chemotherapy (40.9% vs. 48.2%, p = 0.02), and more likely to receive adjuvant endocrine therapy (19.5% vs. 12.6%, p = 0.002). At a median follow-up of 5.1 years, patients with ER-positive 1–10% had worse RFS, DFS and OS rates compared to patients with ER-positive tumors ≥ 10%. The RFS, DFS and OS rates between patients with ER-positive 1–10% and ER negative did not differ significantly. Patients with ER-positive 1–10% and negative still had worse RFS, DSS and OS rates compared to patients with ER-positive tumors ≥ 10% after adjusted by clinical stage, adjuvant chemo and endocrine therapy. Conclusion. Patients whose tumors are ER-positive at 1–10% have clinical and pathologic characteristics different from those whose tumors are ER-positive ≥10%. Similar to patients whose tumors are ER negative, those with ER-positive disease at 1–10% do not appear to benefit from endocrine therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-09.